The major affective illnesses are a set of debilitating diseases which may affect as many as one individual in five in the course of a lifetime. The results of family, twin, and adoption studies indicate that there are clear genetic components underlying both major subtypes of the disease - bipolar and unipolar disorders. However, the exact modes of inheritance and the chromosomal location(s) of the gene(s) contributing to the pathophysiology of these disorders is unknown. The long-term objective of this research effort is to characterize at the molecular level the gene(s) involved in the etiology of early-onset, recurrent, non-psychotic, unipolar depression. By focusing attention on a severe clinical manifestation of major depression, is our intent to maximize the potential genetic load, while diminishing phenotypic and genetic heterogeneity. The experimental Strategies to be employed are designed to complement the ongoing NIMH-sponsored national consortium for genetic investigation of bipolar disorder a and schizophrenia (RFA MH-89-05). The specific aims of the investigation are four fold: (l) To recruit a sample of one hundred nuclear families ascertained through early-onset (less than or equal to 25 years), recurrent (3 episodes) depressive probands. Families recruited for study will contain two living parents and at least one additional sibling. This clinical sample will provide the means (a) to conduct linkage analyses using both affected sib-pair and lod score methodologies, (b) serve as a resource to identify large, highly informative multigenerational pedigrees suitable for both linkage and segregation analyses, and (c) to facilitate tide assessment of genetic heterogeneity once putative linkages are established; (2) To investigate the genetic parameters and mode of inheritance of recurrent depression by complex segregation analysis; (3) To conduct a systematic genome search for genes underlying disease susceptibility using a battery of highly polymorphic DNA markers. Initially, markers located adjacent to genes that could play a significant role in the pathophysiology of major depression will be evaluated; and (4) To initiate longitudinal family studies to assess the stability of psychiatric diagnoses over time, and evaluate the effects of phenotypic instability on genetic analyses. The successful completion of this study may (a) provide verification of the genetic nature of recurrent depression, (b) clarify the inheritance pattern(s) of the disease, (c) generate new information on the genetic components underlying early-onset recurrent depression, (d) lay the foundation for the isolation and characterization of the genes augmenting disease susceptibility, and (e) provide a national resource for future genetic analysis, enabling the community to rapidly evaluate newly established linkages for commonalities and/or differences in the genetic etiology of the major psychiatric disorders and within affective disorder subtypes.